Melatonin is a ubiquitous indolamine, largely investigated for its key role in the regulation of several physiological processes in both animals and plants. In the last century, it was reported that this molecule may be produced in high concentrations by several species belonging to the plant kingdom and stored in specialized tissues. In this review, the main information related to the chemistry of melatonin and its metabolism has been summarized. Furthermore, the biosynthetic pathway characteristics of animal and plant cells have been compared, and the main differences between the two systems highlighted. Additionally, in order to investigate the distribution of this indolamine in the plant kingdom, distribution cluster analysis was performed using a database composed by 47 previously published articles reporting the content of melatonin in different plant families, species and tissues. Finally, the potential pharmacological and biostimulant benefits derived from the administration of exogenous melatonin on animals or plants via the intake of dietary supplements or the application of biostimulant formulation have been largely discussed.

• N-acetyl-5-methoxytriptamine
• biostimulant
• cluster analysis
• dietary supplements
• indolamine

• Animals
• Cluster Analysis
• Dietary Supplements
• Indoles/metabolism
• Melatonin/metabolism
• Plants/metabolism

• ADSCs, Multipotent adipose-derived stem cells
• ALT, Alanine transaminase
• AST, Aspartate transaminase
• Adipose-derived mesenchymal stem cells
• Animal model
• CCL4, Carbon tetracholoride
• CNS, Central nervous system
• EDTA, Ethylenediaminetetraacetic acid
• FBS, Fetal bovine serum
• HGF, Hepatocyte growth factor
• Hepatic cirrhosis
• IM, Intramuscular
• IP, Intraperitoneal
• Liver fibrosis
• MSCs, Mesenchymal stem cells
• PBS, Phosphate buffered saline
• VEGF, Vascular endothelial growth factor
• α-MEM, Minimum essential medium α

• Caffeine
• IL-6
• NAFLD
• Oxygen consumption
• STAT3
• Skeletal muscle

• Adipocytes/metabolism
• Animals
• Caffeine/metabolism
• Caffeine/pharmacology
• Diet, High-Fat
• Disease Models, Animal
• Hepatocytes/metabolism
• Interleukin-6/metabolism
• Interleukin-6/physiology
• Lipid Metabolism/physiology
• Liver/drug effects
• Liver/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Skeletal/drug effects
• Muscle, Skeletal/metabolism
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/physiopathology
• STAT3 Transcription Factor/metabolism
• Signal Transduction/drug effects

In the therapeutic strategies, the role of diet is a well-established factor that can also have an important role in liver diseases. Melatonin, identified in animals, has many antioxidant properties and it was after discovered also in plants, named phytomelatonin. These substances have a positive effect during aging and in pathological conditions too. In particular, it is important to underline that the amount of melatonin produced by pineal gland in human decreases during lifetime and its reduction in blood could be related to pathological conditions in which mitochondria and oxidative stress play a pivotal role. Moreover, it has been indicated that melatonin/phytomelatonin containing foods may provide dietary melatonin, so their ingestion through balanced diets could be sufficient to confer health benefits. In this review, the classification of liver diseases and an overview of the most important aspects of melatonin/phytomelatonin, concerning the differences among their synthesis, their presence in foods and their role in health and diseases, are summarized. The findings suggest that melatonin/phytomelatonin supplementation with diet should be considered important in preventing different disease settings, in particular in liver. Currently, more studies are needed to strengthen the potential beneficial effects of melatonin/phytomelatonin in liver diseases and to better clarify the molecular mechanisms of action.

• diet
• liver
• melatonin
• mitochondria
• oxidative stress
• phytomelatonin

• Animals
• Dietary Supplements
• Humans
• Inflammation Mediators/metabolism
• Liver/metabolism
• Liver/pathology
• Liver Diseases/diagnosis
• Liver Diseases/diet therapy
• Liver Diseases/metabolism
• Liver Diseases/prevention & control
• Melatonin/administration & dosage
• Melatonin/metabolism
• Mitochondria, Liver/metabolism
• Mitochondria, Liver/pathology
• Oxidative Stress

• Caffeine
• Coffee
• HCV
• HIV
• Inflammation
• Liver
• Polyphenols
• Survival

Kahweol is a diterpene molecule found in Coffea Arabica beans. Previous studies have shown that coffee reduces liver fibrosis, but it is not clear which component of coffee has the protective effect. In this study, we examined whether kahweol has a protective effect on hepatic fibrosis in vivo and in vitro. Kahweol decreased hepatic fibrosis by inhibiting connective tissue growth factor (CTGF) expression in thioacetamide (TAA)-treated mice. The expression of phospho-Smad3, signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinases (ERK), and c-Jun N-terminal protein kinase (JNK) increased in the livers of TAA-treated mice and decreased in the kahweol-treated group. Kahweol significantly decreased the expression of transforming growth factor beta (TGF-β)-stimulated type I collagen and CTGF expression in vitro. In addition, kahweol significantly decreased the expression of Smad3, STAT3, ERK and JNK, which are involved in the induction of CTGF expression by TGF-β in hepatocytes, but not in HSCs. These results suggest that kahweol may be a new candidate for treatment of liver fibrosis.

• CTGF
• TGF-β
• hepatic fibrosis
• kahweol

• CTGF
• Cirrhosis
• Coffee
• Oxidative stress
• TGF-β

There is emerging evidence for the positive effects or benefits of coffee in patients with liver disease. We conducted a retrospective cross-sectional study on patients with non-alcoholic fatty liver disease (NAFLD), hepatitis C virus (HCV), and hepatitis B virus (HBV) infection to determine the effects of coffee intake on a non-invasive marker of liver fibrosis: liver stiffness assessed by transient elastography (TE). We assessed coffee and tea intake and measured TE in 1018 patients with NAFLD, HCV, and HBV (155 with NAFLD, 378 with HCV and 485 with HBV). Univariate and multivariate regression models were performed taking into account potential confounders. Liver stiffness was higher in males compared to females (p < 0.05). Patients with HBV had lower liver stiffness than those with HCV and NAFLD. After adjustment for age, gender, smoking, alcohol consumption, M or XL probe, and disease state (NAFLD, HCV, and HBV status), those who drank 2 or more cups of coffee per day had a lower liver stiffness (p = 0.044). Tea consumption had no effect (p = 0.9). Coffee consumption decreases liver stiffness, which may indicate less fibrosis and inflammation, independent of disease state. This study adds further evidence to the notion of coffee maybe beneficial in patients with liver disease.

• coffee
• elastography
• functional foods
• liver disease

• Adult
• Aged
• Body Mass Index
• Body Weight
• Coffee
• Cross-Sectional Studies
• Female
• Hepatitis B/physiopathology
• Hepatitis C/physiopathology
• Humans
• Liver/pathology
• Male
• Middle Aged
• Multivariate Analysis
• Non-alcoholic Fatty Liver Disease/physiopathology
• Retrospective Studies
• Risk Factors
• Tea

• 8-hydroxy deoxyguanosine
• Cycloxygenase-2
• Date Fruits
• Liver fibrosis
• Matrix metalloproteinase
• Nuclear factor-kappa B

• Animals
• Carbon Tetrachloride/toxicity
• Cyclooxygenase 2/metabolism
• DNA Damage/drug effects
• Fruit/chemistry
• Heme Oxygenase-1/metabolism
• Liver/drug effects
• Liver/pathology
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/metabolism
• Male
• NF-kappa B/metabolism
• Phoeniceae/chemistry
• Plant Extracts/chemistry
• Plant Extracts/pharmacology
• Protective Agents/chemistry
• Protective Agents/pharmacology
• Rats
• Rats, Wistar
• Tissue Inhibitor of Metalloproteinases/metabolism

• National Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia

Growing evidence has shown that coffee consumption is inversely related with the risk of hepatocellular carcinoma. It is suggested that caffeine maintains strong antioxidative activity. With this property, coffee intake may lead to the inhibition of cell proliferation of liver cancer cells; also, some compounds contained in coffee can reduce the genotoxicity of aflatoxin B1 in vitro and lower the damage caused by some carcinogens. A computerized search was performed in PubMed to identify relevant articles published before August 2015. Eleven relevant studies were included with a total of 2,795 cases and 340,749 control subjects. According to the meta-analysis we performed, the pooled odds ratio (OR) from all included studies was 0.49 (95% confidence interval [CI] =0.46–0.52). The subgroup analysis indicated that the pooled ORs for Asian studies and other populations were 0.27 (95% CI =0.23–0.31) and 0.82 (95% CI =0.77–0.87), respectively. The overall pooled OR for high consumption was decreased to 0.21 (95% CI =0.18–0.25) and significance was observed. Among other populations, the pooled OR of subjects with high coffee consumption was 0.65 (95% CI =0.56–0.73) compared to the nondrinker. The corresponding OR of five Asian studies was 0.13 (95% CI =0.09–0.17). The findings from this meta-analysis further confirmed the inverse association between the coffee consumption and hepatocellular carcinoma risk with quantitative evidence. The protective effect can be detected among healthy population and patients with chronic liver diseases, and the consumption can also prevent the development of liver cirrhosis.

• antioxidant
• coffee
• hepatocarcinogenesis
• meta-analysis

Hepatic fibrosis and cirrhosis cause strong human suffering and necessitate a monetary burden worldwide. Therefore, there is an urgent need for the development of therapies. Pre-clinical animal models are indispensable in the drug discovery and development of new anti-fibrotic compounds and are immensely valuable for understanding and proofing the mode of their proposed action. In fibrosis research, inbreed mice and rats are by far the most used species for testing drug efficacy. During the last decades, several hundred or even a thousand different drugs that reproducibly evolve beneficial effects on liver health in respective disease models were identified. However, there are only a few compounds (e.g., GR-MD-02, GM-CT-01) that were translated from bench to bedside. In contrast, the large number of drugs successfully tested in animal studies is repeatedly tested over and over engender findings with similar or identical outcome. This circumstance undermines the 3R (Replacement, Refinement, Reduction) principle of Russell and Burch that was introduced to minimize the suffering of laboratory animals. This ethical framework, however, represents the basis of the new animal welfare regulations in the member states of the European Union. Consequently, the legal authorities in the different countries are halted to foreclose testing of drugs in animals that were successfully tested before. This review provides a synopsis on anti-fibrotic compounds that were tested in classical rodent models. Their mode of action, potential sources and the observed beneficial effects on liver health are discussed. This review attempts to provide a reference compilation for all those involved in the testing of drugs or in the design of new clinical trials targeting hepatic fibrosis.

• 3R principle
• animal experimentation
• clinical trials
• collagen
• hepatic fibrosis
• therapy
• translational medicine
• α-smooth muscle actin

• Antioxidant
• Coffee
• Curcumin
• Liver diseases
• Naringenin
• Oxidative stress
• Quercetin
• Resveratrol
• Silymarin

Evidence demonstrating that regular ingestion of coffee has salutary effects on patients with chronic liver disease is accumulating rapidly. Specifically, it appears that coffee ingestion can slow the progression of liver fibrosis, preventing cirrhosis and hepatocellular carcinoma (HCC). This should excite clinicians and scientists alike, since these observations, if true, would create effective, testable hypotheses that should lead to improved understanding on fibrosis pathogenesis and thus may generate novel pharmacologic treatments of patients with chronic liver disease.

This review is designed to examine the relevant clinical and epidemiological data in critical fashion and to examine the putative pharmacological effects of coffee relevant to the pathogenesis of liver fibrosis and cirrhosis. We hope that this will inspire relevant critical analyses, especially among “coffee skeptics”. Of note, one major assumption made by this review is that the bulk of the effects of coffee consumption are mediated by caffeine, rather than by other chemical constituents of coffee. Our rationales for this assumption are threefold: first, caffeine’s effects on adenosinergic signaling provide testable hypotheses; second, although there are  myriad chemical constituents of coffee, they are present in very low concentrations, and perhaps more importantly, vary greatly between coffee products and production methods (it is important to note that we do not dismiss the “botanical” hypothesis here; rather, we do not emphasize it at present due to the limitations of the studies examined); lastly, some (but not all) observational studies have examined both coffee and non-coffee caffeine consumption and found consistent effects, and when examined, no benefit to decaffeinated coffee has been observed. Further, in the interval since we examined this phenomenon last, further evidence has accumulated supporting caffeine as the effector molecule for coffee’s salutary effects.

• adenosine receptor
• cirrhosis
• coffee
• liver fibrosis

Previous data indicated the protective effect of date fruit extract on oxidative damage in rat liver. However, the hepatoprotective effects via other mechanisms have not been investigated. This study was performed to evaluate the antifibrotic effect of date flesh extract (DFE) or date pits extract (DPE) via inactivation of hepatic stellate cells (HSCs), reducing the levels of inflammatory, fibrotic and angiogenic markers. Coffee was used as reference hepatoprotective agent. Liver fibrosis was induced by injection of CCl₄ (0.4 mL/kg) three times weekly for 8 weeks. DFE, DPE (6 mL/kg), coffee (300 mg/kg), and combination of coffee + DFE and coffee + DPE were given to CCl₄-intoxicated rats daily for 8 weeks. DFE, DPE, and their combination with coffee attenuated the elevated levels of inflammatory cytokines including tumor necrosis factor-α, interleukin-6, and interleukin-1β. The increased levels of transforming growth factor-β1 and collagen deposition in injured liver were alleviated by both extracts. CCl₄-induced expression of α-smooth muscle actin was suppressed indicating HSCs inactivation. Increased angiogenesis was ameliorated as revealed by reduced levels and expression of vascular endothelial growth factor and CD31. We concluded that DFE or DPE could protect liver via different mechanisms. The combination of coffee with DFE or DPE may enhance its antifibrotic effects.

• metabolomics
• physical activity
• diet
• network analysis
• systems epidemiology

• Amino Acids/blood
• Biomarkers/blood
• Body Mass Index
• Carbohydrates/blood
• Carnitine/analogs & derivatives
• Carnitine/blood
• Coffee
• Diet
• Energy Metabolism
• Exercise
• Feeding Behavior
• Female
• Germany/epidemiology
• Humans
• Life Style
• Male
• Metabolome
• Middle Aged
• Obesity/blood
• Obesity/epidemiology
• Obesity/etiology
• Obesity/prevention & control
• Phospholipids/blood
• Physical Fitness
• Population Surveillance
• Prospective Studies
• Risk Factors
• Waist Circumference

• Blood
• Olive leaves
• Rats
• Rosemary leaves
• Thioacetamide

• coffee
• caffeine
• tea
• alcohol
• cirrhosis

• Alcohol Drinking/mortality
• Asian People/statistics & numerical data
• Beverages
• Carbonated Beverages
• Coffee
• Feeding Behavior
• Female
• Humans
• Liver Cirrhosis/mortality
• Male
• Middle Aged
• Proportional Hazards Models
• Prospective Studies
• Risk Factors
• Singapore/epidemiology
• Tea

• R01 CA080205 NCI NIH HHS
• R01 CA144034 NCI NIH HHS
• R35 CA053890 NCI NIH HHS
• R01 CA80205 NCI NIH HHS

• Coffee
• Pregnancy
• Primary Sclerosing Cholangitis
• Smoking

• Caffeine
• Coffee beverages
• Liver fibrosis and carcinogenesis
• Prevention

The purpose of this study is to investigate the effect of Ginkgo biloba leaves extract on experimental liver fibrosis induced by thioacetamide (TAA) in male albino mice. The experimental mice were divided into four groups. The mice of the first group were served as control. The experimental animals of the second group were given 150 mg/kg body weight of TAA by intraperitoneal injection, twice weekly, for 9 weeks. The mice of the third group were exposed to TAA and supplemented with G. biloba leaves extract. The animals of the fourth group were supplemented with G. biloba leaves extract. The levels of plasma alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, triglycerides, cholesterol, and low-density lipoprotein cholesterol were statistically increased while the levels of plasma total protein, albumin, glucose, and high-density lipoprotein cholesterol were significantly decreased. The levels of liver superoxide dismutase, glutathione, glycogen and total protein were notably declined, whereas the level of total lipid was increased in mice of the second group. Furthermore, microscopic examination of liver sections from mice treated with TAA showed an abnormal morphology characterized by nodular transformations in liver parenchyma which surrounded by fibrous septa. Administration of G. biloba leaves extract reduced extent and development of fibrous septa, liver cells change, and biochemical alterations in mice exposed to TAA. This study showed that G. biloba leaves extract has a potential activity against TAA-induced liver fibrosis and suggested that the chemical constituents of G. biloba are effective in modulation of oxidative stress induced by TAA.